U.S. patent application number 14/800000 was filed with the patent office on 2017-02-16 for salt compound.
The applicant listed for this patent is SGC PHARMA, INC.. Invention is credited to Robert Bender, Ho-Lun Joseph CHAU, Doug Cowart.
Application Number | 20170044118 14/800000 |
Document ID | / |
Family ID | 45723790 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170044118 |
Kind Code |
A1 |
Bender; Robert ; et
al. |
February 16, 2017 |
SALT COMPOUND
Abstract
A salt compound, and methods for mitigating neurodegeneration,
effecting, neuroprotection and/or effecting cognition enhancement
in a subject using the salt compound are described. Neurological or
cognitive conditions are treated by administering to a subject an
effective amount of a therapeutic salt compound comprising, a
nitrate ester.
Inventors: |
Bender; Robert; (Ottawa,
CA) ; CHAU; Ho-Lun Joseph; (Whistler, CA) ;
Cowart; Doug; (North Potomac, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SGC PHARMA, INC. |
Ottawa |
|
CA |
|
|
Family ID: |
45723790 |
Appl. No.: |
14/800000 |
Filed: |
July 15, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13818410 |
Jun 5, 2013 |
9114135 |
|
|
PCT/US2011/048966 |
Aug 24, 2011 |
|
|
|
14800000 |
|
|
|
|
61376501 |
Aug 24, 2010 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/426 20130101;
A61P 25/00 20180101; C07C 57/145 20130101; A61P 9/00 20180101; C07D
277/24 20130101; A61K 31/194 20130101; A61P 25/28 20180101; C07D
277/28 20130101 |
International
Class: |
C07D 277/28 20060101
C07D277/28; C07C 57/145 20060101 C07C057/145 |
Claims
1. The maleate salt of the compound ##STR00008##
2. A pharmaceutical composition comprising the maleate salt of the
compound ##STR00009## together with a pharmaceutically acceptable
diluent or carrier.
3. A dry tablet composition comprising the maleate salt of the
compound ##STR00010## and a pharmaceutically acceptable diluent or
carrier.
4. The dry tablet of claim 3, formulated for oral
administration.
5. A method for inhibiting neurodegeneration, or effecting
neuroprotection in a subject in need thereof, said method
comprising administering to said subject an effective amount of a
composition of claim 1, such that said neurodegeneration is
inhibited or said neuroprotection is effected.
6. The method of claim 5, wherein administering the therapeutic
compound to said subject modulates levels of cyclic nucleotide cGMP
and/or cAMP.
7. The method of claim 5, wherein said neurodegeneration or said
neuroprotection is associated with a condition selected from the
group consisting of stroke, Parkinson's disease, Alzheimer's
disease, Huntington's disease, multiple sclerosis, amyotrophic
lateral sclerosis, AIDS-induced dementia, epilepsy, alcoholism,
alcohol withdrawal, drug-induced seizure,
viral/bacterial/fever-induced seizure, trauma to the head,
hypoglycemia, hypoxia, myocardial infarction, cerebral vascular
occlusion, cerebral vascular hemorrhage, hemorrhage, an
environmental excitotoxin, dementia, trauma, drug-induced brain
damage, and aging.
8. The method of claim 5, wherein said neurodegeneration or said
neuroprotection is associated with dementia.
9. The method of claim 5, wherein said neurodegeneration or said
neuroprotection is associated with Alzheimer's disease.
10. The method of claim 5, wherein said composition inhibits
dementia.
11. The method of claim 5, wherein said composition inhibits
Alzheimer's disease.
12. A method for effecting cognition enhancement in a subject in
need thereof comprising administering to said subject an effective
amount a composition of claim 1.
13. A method for mitigating cerebral damage due to ischemia in a
subject in need thereof comprising administering to said subject an
effective amount of a composition of claim 1, such that cerebral
damage is mitigated.
14. The method of claim 5, wherein said composition is administered
orally.
15. A method for inhibiting neurodegeneration, or effecting
neuroprotection in a subject in need thereof, said method
comprising administering to said subject an effective amount of a
composition of claim 2, such that said neurodegeneration is
inhibited or said neuroprotection is effected.
16. A method for inhibiting neurodegeneration, or effecting
neuroprotection in a subject in need thereof, said method
comprising administering to said subject an effective amount of a
composition of claim 3, such that said neurodegeneration is
inhibited or said neuroprotection is effected.
17. A method for inhibiting neurodegeneration, or effecting
neuroprotection in a subject in need thereof, said method
comprising administering to said subject an effective amount of a
composition of claim 4, such that said neurodegeneration is
inhibited or said neuroprotection is effected.
18. The method of claim 12, wherein said composition is
administered orally.
19. The method of claim 13, wherein said composition is
administered orally.
20. The maleate salt of claim 1, having the XRPD graphic scan of
FIG. 1.
Description
RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application No. 61/376,501, Attorney Docket No. SGCI-003-1, filed
Aug. 24, 2010, entitled "SALT COMPOUND." The contents of any
patents, patent applications, and references cited throughout this
specification are hereby incorporated by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] The compound 2-(4-methylthiazol-5-yl)ethyl nitrate:
##STR00001##
is known to interact with amino acid neurotransmitter receptors
such as the NMDA receptor and the .gamma.-aminobutyric acid type A
(GABA.sub.A) receptor. This compound is also known to stimulate
cerebral soluble guanylyl cyclase (GCase). As such, this compound
is useful for its neuroprotective properties, and effecting
cognition enhancement. See, e.g., U.S. Pat. No. 6,310,052. It has
been found that new solid forms of 2-(4-methylthiazol-5-yl)ethyl
nitrate can be prepared as the maleate salt form. This salt form
exhibits new physical properties that can be exploited in order to
achieve new properties, making it useful as a drug substance.
SUMMARY OF INVENTION
[0003] Accordingly, the present invention provides the maleate salt
of the compound
##STR00002##
(also referred to herein as "2-(4-methylthiazol-5-yl)ethyl nitrate
maleate salt," "the maleate salt of 2-(4-methylthiazol-5-yl)ethyl
nitrate," or "the salt compound"). Another object of the present
invention is to provide methods for making
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt. Another object
of the invention is to provide methods for effecting
neuroprotection, mitigating neurodegeneration and/or effecting
cognition enhancement employing 2-(4-methylthiazol-5-yl)ethyl
nitrate maleate sail. Another object of the present invention is to
provide 2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt as a
neuroprotective agent. Yet another object of the present invention
is to provide 2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt
for use in cognition enhancement.
[0004] In another aspect, provided herein is a pharmaceutical
composition comprising the maleate salt of the compound
##STR00003##
together with a pharmaceutically acceptable diluent or carrier.
[0005] Also provided herein is a dry tablet composition comprising
the maleate salt of the compound
##STR00004##
and a pharmaceutically acceptable diluent or carrier. The dry
tablet can be formulated for oral administration.
[0006] In still another aspect, provided herein is a method for
inhibiting neurodegeneration, or effecting neuroprotection in a
subject in need thereof, said method comprising administering to
said subject an effective amount of the salt compound or
pharmaceutical composition described above, such that said
neurodegeneration is inhibited or said neuroprotection is affected.
In one embodiment, administering the therapeutic compound to said
subject modulates levels of cyclic nucleotide cGMP and/or cAMP.
[0007] The neurodegeneration or said neuroprotection that is
treated can be associated. with a condition selected from the group
consisting of stroke, Parkinson's disease, Alzheimer's disease,
Huntington's disease, multiple sclerosis, amyotrophic lateral
sclerosis, AIDS-induced dementia, epilepsy, alcoholism, alcohol
withdrawal, drug-induced seizure, viral/bacterial/fever-induced
seizure, trauma to the head, hypoglycemia, hypoxia, myocardial
infarction, cerebral vascular occlusion, cerebral vascular
hemorrhage, hemorrhage, an environmental excitotoxin, dementia,
trauma, drug-induced brain damage, and aging. In another
embodiment, said neurodegeneration or said neuroprotection is
associated with dementia. In still another embodiment, said
neurodegeneration or said neuroprotection is associated with
Alzheimer's disease.
[0008] In one embodiment, the salt compound or pharmaceutical
composition inhibits dementia. In another embodiment the salt
compound or pharmaceutical composition inhibits Alzheimer's
disease. Thus, in one embodiment, provided herein is a method of
treating Alzheimer's disease in a subject in need thereof,
comprising administering to the subject an effective amount of the
maleate salt of 2-(4-methylthiazol-5-yl)ethyl nitrate.
[0009] In another embodiment, provided herein is a method for
effecting cognition enhancement in a subject in need thereof
comprising administering to said subject an effective amount the
salt compound or pharmaceutical composition described above.
[0010] In another aspect, provided herein is a method for
mitigating cerebral damage due to ischemia in a subject in need
thereof comprising administering to said subject an effective
amount of the salt compound or pharmaceutical composition described
above, such that cerebral damage is mitigated.
[0011] In certain embodiments of the treatments described above,
the salt compound or pharmaceutical composition is administered
orally. In a particular embodiment of these treatments, the salt
compound or pharmaceutical composition is administered in as a dry
tablet.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows an XRPD graphic scan of
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt.
DETAILED DESCRIPTION OF INVENTION
[0013] This invention pertains to a salt compound useful for
treating neurodegeneration. The methods of the invention involve
administering to a subject 2(4-methylthiazol-5-yl)ethyl nitrate
maleate salt, which effects neuroprotection and/or cognition
enhancement. Without being bound by theory, neuroprotection and/or
cognition enhancement can be effected, for example, by modulating
an interaction with guanylyl cyclase (GCase), a glutamate or
non-glutamate neuroreceptor or attenuating free radical damage.
GCase is the enzyme responsible for cGMP production in various
areas of the brain.
[0014] Neurodegeneration is mitigated by stimulating cerebral
GCase. One of the major targets for organic nitrates is GCase
activation, resulting in the production of cGMP. Experimental
evidence obtained in a number of in vitro model systems supports
the notion that elevated levels of cGMP help to prevent apoptotic
(programmed) cell death. Thus, a cGMP-dependent mechanism
significantly increases the survival of trophic factor-deprived.
PC12 cells and rat sympathetic neurons (Farinelli et al., 1996),
and of primary cultures of rat embryonic motor neurons (Estevez et
al., 1998). The mechanism of action for organic nitrates in
preventing apoptotic cell death may be inhibition of caspase-3
activation indirectly through elevations in cGMP levels or directly
via protein S-nitrosylation of the enzyme by an NO-intermediate
(Kim et al., 1997). Caspase-3 is a member of the cysteine protease
family of enzymes that are essential for the execution step in
apoptosis (Cohen, 1997; Nicholson and Thornberry, 1997). Activation
of caspase-3 is required for apoptotic cell death in trophic
factor-deprived PC12 cells (Haviv et al., 1997) and in
glutamate-mediated apoptotic cell death of cultured cerebellar
granule neurons (Du et at., 1997). In animal models of cerebral
ischemia, caspase-3 activity is induced and may be responsible for
the apoptotic component of delayed neuronal cell death (Chen et
al., 1998;. Namura et al., 1998; Ni et at., 1998). Inhibitors of
caspase-3 significantly decrease the apoptotic component of delayed
neuronal cell death in response to ischemic injury both in vitro
(Gottron et at., 11997) and in vivo (Endres et at,, 1998). A
secreted region of the Alzheimer's disease .beta.-amyloid precursor
protein lowers intracellular calcium levels and provides
neuroprotective effects on target cells through increases in cGMP
levels and activation of protein kinase G (Barger et al., 1995;
Furukawa et al., 1996). In preferred embodiments of the methods of
the invention, the salt compound has the capacity to activate GCase
directly or via release of an NO-containing intermediate are used
to modulate GCase activity.
[0015] According to certain other aspects of the invention,
cognition enhancement (e.g., improved memory performance) is
achieved by stimulating cerebral GCase. Several lines of
experimental evidence support the notion that GCase and cGMP are
involved in the formation and retention of new information. cGMP
has been directly implicated in both long-term potentiation (LTP)
and long-term depression (LTD), which are proposed cellular models
for learning and memory (Arancio et al., 1995; Wu et al., 1998). In
animal models, elevation of hippocampal cGMP levels leading to
increased protein kinase G activity has been shown to be important
for retention and consolidation of new learning (Bernabeu et al,,
1996, 1997). Thus, stimulation of cerebral GCase activity is
expected to improve learning and memory performance in individuals
in whom cognitive abilities are impaired by injury, disease, or
aging.
[0016] Organic nitrate esters have differential effects to activate
soluble GCase and to cause cGMP accumulation in vascular and brain
tissue (see, e.g., U.S. Pat. No. 6,310,052). There is a clear
dissociation between the vascular relaxation effects of organic
nitrate esters and ability to effect neuroprotection. Activation of
GCase and accumulation of cGMP have been shown to be important in
the neuroprotection of hippocampal brain slices subjected to a
period of in vitro ischemia.
[0017] Cerebral ischemia results in marked increases in the release
of the excitatory amino acid glutamate in the affected brain region
(Bullock et al., 1998; Huang et al., 1998; Yang et at., 1998). In
both humans (Bullock et al., 1998) and experimental animals (Huang
et al., 1998; Coda et at., 1998; Yang et al., 1998), the amount of
glutamate released during ischemia is positively correlated with
the extent of brain injury. In experimental animal models of
cerebral ischemia, decreased release of glutamate during ischemia
(Coda et al., 1998) or blockade of glutamate receptors with
antagonists (Ibarrola et at., 1998; O'Neill et al., 1998; Umemura
et al., 1997) significantly reduces the extent of brain injury.
However, these interventions are only effective when given prior to
or during the ischemic insult. To be broadly useful, a therapeutic
intervention is preferably effective when administered after the
period of ischemia.
[0018] Accordingly, the salt compound provided herein can be used
for treatment of conditions including, but not limited to: stroke;
Parkinson's disease; Alzheimer's disease; Huntington's disease;
multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced
dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced
seizures; viral/bacterial/fever-induced seizures; trauma to the
head; hypoglycemia; hypoxia; myocardial infarction; cerebral
vascular occlusion; cerebral vascular hemorrhage; hemorrhage;
environmental excitotoxins of plant, animal and marine origin; and
the like.
[0019] The direct effects of organic nitrates on amino acid
neurotransmitter receptors has been tested using the Xenopus oocyte
expression system and two-electrode voltage-clamp recording methods
(see, e.g., U.S. Pat. No. 6,310,052). Organic nitrates have been
found to have direct, modulatory effects on GABA.sub.A receptor
function, These allosteric modulatory effects of organic nitrates
were not shared by direct NO-generating compounds, indicating a
novel mechanism of action for organic nitrates to interact with
GABA.sub.A receptors. In behavioural models of learning and memory,
drugs which decrease GABA.sub.A receptor function improve
performance on learning and memory tasks (Venault et al 1992).
Thus, the behavioural effect of organic nitrates, developed to act
as modulators of GABA.sub.A receptor function, will be to improve
memory performance and cognition in patient populations. It will be
appreciated, therefore, that these organic nitrates can be used for
treatment of conditions including but not limited to: stroke;
dementias of all type; trauma; drug-induced brain damage; and
aging.
[0020] According to certain aspects of the invention,
neurodegeneration is mitigated by inhibition of free radical
damage. Reoxygenation and reperfusion after a period of ischemia
contributes significantly to the development of brain injury.
Oxygen radicals, especially superoxide and peroxynitrite, formed in
the period after an ischemic event may initiate processes such as
breakdown of membrane lipids (lipid peroxidation), leading, to loss
of cell membrane integrity and inhibition of mitochondrial function
(Macdonald and Stoodley, 1998; Gaetani e at, 1998). Oxidative
stress is also believed to be one factor involved in initiation of
apoptotic neuronal cell death (Tagami et al 1998). In experimental
animal models of ischemic brain injury, free radical scavengers and
enhanced activity of superoxide dismutase have been found to reduce
the extent of neuronal injury and cell death (Chan et al., 1998;
Mizuno et al., 1998; Tagami et al., 1998). In preferred embodiments
of the methods of the invention, the slat compound has the capacity
to inhibit production of free radicals and/or act as a free radical
scavenger, thereby attenuating the brain injury that occurs after a
period of cerebral ischemia. It will be appreciated by those
skilled in the art, that any organic nitrate in which vasodilatory
potency is reduced and neuroprotective potency increased,
represents a new and useful therapeutic agent for use in
neuroprotection, particularly in treatment of conditions including
but not limited to: stroke; Parkinson's disease; Alzheimer's
disease; Huntington's disease; multiple sclerosis; amylotrophic
lateral sclerosis; AIDS-induced dementia; epilepsy; alcoholism;
alcohol withdrawal; drug-induced seizures;
viral/bacterial/fever-induced seizures; trauma to the head;
hypoglycemia; hypoxia; myocardial infarction; cerebral vascular
occlusion; cerebral vascular hemorrhage; hemorrhage; environmental
excitotoxins of plant, animal and marine origin. GTN proposed as a
neuroprotective agent, has no clinical utility as a neuroprotective
agent in therapy owing to its extraordinarily high vasodilatory
potency. Similarly, by extrapolation, 1,2,3-trinitratopropane (GTN)
derivatives are not expected to have clinical utility as
neuroprotective agents in therapy owing to their especially high
vasodilatory potency.
[0021] It will additionally be appreciated by those skilled in the
art that the use in therapy of 2-(4-methylthiazol-5-yl)ethyl
nitrate maleate salt in cognition enhancement, represents a new and
useful treatment for cognition enhancement, particularly in
treatment of conditions including but not limited to: stroke:
dementias of all type, trauma, drug-induced brain damage, and
aging.
[0022] "Mitigating neurodegeneration" as used herein involves
effecting neuroprotection, inhibiting or preventing
neurodegeneration, and/or ameliorating the manifestations or impact
of neurodegeneration. Such amelioration includes effecting
cognition enhancement, as is quantified by tests known in the art
(e.g., Venault et al., 1992, incorporated herein by reference).
"Modulating" a biological process as used herein (for example,
modulating the activity of the non-glutamate neuroreceptors),
encompasses both increasing (positively moduclating) and
decreasing, (negatively modulating) such activity, and thus
inhibition, potentiation, agonism, and antagonism of the biological
process.
[0023] In one aspect, the invention provides a method of treating a
neurological condition and/or preventing an undesirable mental
condition (e.g., memory loss) including the step of administering
to a subject an effective amount of 2-(4-methylthiazol-5-yl)ethyl
nitrate maleate salt. In one embodiment, the therapeutic compound
is capable of effecting neuroprotection. In another embodiment of
the invention, the therapeutic compound is capable of effecting
cognition enhancement.
[0024] In the methods of the invention, neurodegeneration in a
subject is mitigated, and/or neuroprotection and/or cognition
enhancement is effected, by administering a therapeutic compound of
the invention to the subject. The term "subject" is intended to
include living organisms in which the particular neurological
condition to be treated can occur, Examples of subjects include
humans, apes, monkeys, cows, sheep, goats, dogs, cats, mice, rats,
and transgenic species thereof. As evidenced by Mordenti (1986) and
similar articles, dosage forms for animals such as, for example,
rats can be and are widely used directly to establish dosage levels
in therapeutic applications in higher mammals, including
humans.
[0025] In particular, the biochemical cascade initiated by cerebral
ischemia is generally accepted to be identical in mammalian species
(Mattson and Scheff, 1994; Higashi et al., 1995). In light of this,
pharmacological agents that are neuroprotective in animal models
such as those described herein are believed to be predictive of
clinical efficacy in humans, after appropriate adjustment of
dosage. Specifically, there are comparable memory-deficit patterns
between brain-damaged rats and humans, which indicates that the rat
can serve as an excellent animal model to evaluate the efficacy of
pharmacological treatments or brain damage upon memory (Kesner,
1990). An approved drag for the clinical treatment of occlusive
stroke in humans is a tissue plasminogen activator, which is
administered at a dose of 0.9 mg/kg by intravenous injection
(Wittkowsky, 1998). This drug is also effective in protecting the
rat brain subjected to cerebral ischemia by occlusion of the middle
cerebral artery, when administered at a dose of 10 mg/kg
intravenously Giang et al., 1998).
[0026] As would also be apparent to a person skilled in the art,
the invention further encompasses methods of the invention employed
ex vivo or in vitro. Also, diagnostic tests or studies of efficacy
of selected compounds may conveniently be performed ex vivo or in
vitro, including in animal models. Such tests, studies and assays
are within the scope of the invention.
[0027] Administration of the salt of the present invention to a
subject to be treated can be carried out using known procedures, at
dosages and for periods of time effective to mitigate
neurodegeneration, and/or to effect neuroprotection and/or
cognition enhancement in the subject. An effective amount of the
therapeutic compound necessary to achieve a therapeutic effect may
vary according to factors such as the amount of neurodegeneration
that has already occurred at the clinical site in the subject, the
age, sex, and weight of the subject, and the ability of the
therapeutic compound to mitigate neurodegeneration and/or to effect
neuroprotection and/or cognition enhancement in the subject. Dosage
regimens can be adjusted to provide the optimum therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation. A non-limiting example of
an effective dose range for a therapeutic salt of the invention is
between 0.5 and 500 mg/kg of body weight per day. In an aqueous
composition, preferred concentrations for the active compound
(i.e., the therapeutic compound that can mitigate neurodegeneration
and/or effect neuroprotection and/or cognition enhancement) are
between 5 and 500 mM, more preferably between 10 and 100 mM, and
still more preferably between 20 and 50 mM.
[0028] The therapeutic compounds of the invention can be effective
when administered orally. Accordingly, a preferred route of
administration is oral administration. Alternatively, the active
compound may be administered by other suitable routes such as
transdermal, subcutaneous, intraocular, intravenous, intramuscular
or intraperitoneal administration, and the like (e.g., by
injection). Depending on the route of administration, the active
compound may be coated in a material to protect the compound from
the action of acids, enzymes and other natural conditions which may
inactivate the compound.
[0029] The compounds of the invention can be formulated to ensure
proper distribution in vivo. For example, the blood-brain barrier
(BBB) excludes many highly hydrophilic compounds. To ensure that
the therapeutic compounds of the invention cross the BBB, they can
be formulated, for example, in liposomes. For methods of
manufacturing liposomes, see, e.g., U.S. Pat. Nos. 4,522.811;
5,374,548; and 5,399,331. The liposomes may comprise one or more
moieties which are selectively transported into specific cells or
organs ("targeting moieties"), thus providing targeted drug
delivery (see, e.g., Ranade et. al., 1989). Exemplary targeting
moieties include folate and biotin (see, e.g., U.S. Pat. No.
5,416,016 to Low et.); mannosides (Umezawa al., 1988); antibodies
(Bloeman et al., 1995; Owais et al., 1995); and surfactant protein
A receptor (Briscoe et al., 1995), In a preferred embodiment, the
therapeutic compounds of the invention are formulated in liposomes;
in a more preferred embodiment, the liposomes include a targeting
moiety.
[0030] It will be appreciated that the ability of a compound of the
invention to mitigate neurodegeneration will, in certain
embodiments, be evaluated by observation of one or more symptoms or
signs associated with neurodegeneration in vivo. Thus, for example,
the ability of a compound to mitigate neurodegeneration may be
associated with an observable improvement in a clinical
manifestation of the underlying neurodegeneration-related disease
state or condition, or a slowing or delay in progression of
symptoms of the condition. Thus, monitoring of clinical
manifestations of disease can be useful in evaluating the
neurodegeneration-mitigating efficacy of a compound of the
invention.
[0031] The method of the invention is useful for treating
neurodegeneration associated with any disease in which
neurodegeneration occurs. Clinically, neurodegeneration can be
associated with conditions including but not limited to: stroke;
Parkinson's disease; Alzheimer's disease; Huntington's disease;
multiple sclerosis; amylotrophic lateral sclerosis; AIDS-induced
dementia; epilepsy; alcoholism; alcohol withdrawal; drug-induced
seizures; viral/bacterial/fever-induced seizures; trauma to the
head; hypoglycemia; hypoxia; myocardial infarction; cerebral
vascular occlusion; cerebral vascular hemorrhage; hemorrhage;
environmental excitotoxins of plant; animal and marine origin;
dementias of all type; trauma; drug-induced brain damage; and
aging; or result from surgical procedures such as cardiac
bypass.
[0032] The term "subject" is intended to include animals, which are
capable of suffering from or afflicted with neurodegeneration.
Examples of subjects include mammals, e.g., humans, dogs, cows,
horses, pigs, sheep, goats, cats, mice, rabbits, rats, and
transgenic non-human animals. In certain embodiments, the subject
is a human, e.g., a human suffering from, at risk of suffering
from, or potentially capable of suffering from
neurodegeneration.
Pharmaceutical Compositions
[0033] The maleate salt compound of the invention can be
administered in a pharmaceutically acceptable vehicle. As used
herein, "pharmaceutically acceptable vehicle" includes any and all
solvents, excipients, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the
like that are compatible with the activity of the compound and are
physiologically acceptable to the subject. An example of the
pharmaceutically acceptible vehicle is buffered normal saline (0.15
M NaCl). The use of such media and agents for pharmaceutically
active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the therapeutic
compound, use thereof in the compositions suitable for
pharmaceutical administration is contemplated. Supplementary active
compounds can also be incorporated into the compositions.
[0034] In a particular embodiment, provided herein is
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt formulated in a
pharmaceutical composition together with a pharmaceutically
acceptable diluent or carrier.
[0035] In one embodiment, the salt compound is formulated into a
dry tablet. The dry tablet can include a mixture of active
substances and excipients, such as excipients in powder form,
pressed or compacted into a solid. Examples of appropriate
excipients for a dry tablet include, but are not limited to,
disintegrants, diluents, lubricants, binders, granulating agents,
glidants, sweeteners or other flavors, and pigments. The dry tablet
can also include a polymer coating that can make the tablet
smoother and easier to swallow, to control the release rate of the
active ingredient, to make it more resistant to the environment
(extending its shelf life), or to enhance the tablet's
appearance.
[0036] The maleate salt provided herein has processing advantages
over other salts (e.g., the chloride, phosphate, mesylate, and
sulfate salts) in the preparation of a dry tablet.
[0037] The dry tablet can be used for oral administration, The dry
tablet can also be administered sublingually, buccally, rectally or
intravaginally.
[0038] The therapeutic compound can be orally administered, for
example, with an inert diluent or an assimilable edible carrier.
The therapeutic compound and other ingredients may also be enclosed
in a hard or soft shell gelatin capsule, compressed into tablets,
or incorporated directly into the subject's diet. For oral
therapeutic administration, the therapeutic compound may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. The percentage of the therapeutic
compound in the compositions and preparations may, of course, be
varied. The amount of the therapeutic compound in such
therapeutically useful compositions is such that a suitable dosage
will be obtained.
[0039] In one embodiment, the maleate salt compound is formulated
with methocel K100M, avicel PH 102, providone, cab-o-sil, and
magnesium stearate. In another embodiment, the pharmaceutical
composition comprises, by weight, 20%-60% methylthiazol-5-yl)ethyl
nitrate maleate salt, 30%-40% methocel K100M, 20%-30% avicel PH
102, 1%-1.5% providone, 0.1%-1% cab-o-sil, and 0.1%-1% magnesium
stearate. In another embodiment, the pharmaceutical composition
comprises, by weight, approximately 30%
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt, approximately
35% methocel K100M, approximately 23% avicel PH 102, approximately
10% providone, approximately 0.25% cab-o-sil, and approximately
0.5% magnesium stearate. In another embodiment, the pharmaceutical
composition comprises, by weight, approximately 40%
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt, approximately
2.5% methocel K100M, approximately 23% avicel PH 102, approximately
10% providone, approximately 0.25% cab-o-sil, and approximately
0.5% magnesium stearate. In a particular embodiment, the
pharmaceutical compositions provided above are formulated into a
dry tablet.
[0040] In another embodiment, the maleate salt compound is
formulated with ethocel 100 premium, avicel PH 102, providone,
cab-o-sil, and magnesium stearate. In another embodiment, the
pharmaceutical composition comprises, by weight, 30%-60%
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt, 20%-50% ethocel
100 premium, 20%-30% avicel PH 102, 1%-15% providone, 0.1%-1%
cab-o-sil, and 0.1%-1% magnesium stearate. In another embodiment,
the pharmaceutical composition comprises, by weight, approximately
40% 2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt,
approximately 25% ethocel 100 premium, approximately 23% avicel PH
102, approximately 10% providone, approximately 0.25% cab-a-sill,
and approximately 0.5% magnesium stearate. In a particular
embodiment, the pharmaceutical compositions provided above are
formulated into a dry tablet.
[0041] The salt compound can also be formulated into a
"controlled-release" formulation, which includes dosage forms whose
drug-release characteristics of time course and/or location are
chosen to accomplish therapeutic or convenience objectives not
offered by conventional dosage forms such as a solution or an
immediate release dosage form. In a particular embodiment, provided
herein is a dry tablet comprising controlled-release formulation of
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt.
[0042] The therapeutic compound may also be administered
parenterally (e.g., intramuscularly, intravenously,
intraperitoneally, intraspinally, or intracerebrally). Dispersions
can be prepared in glycerol, liquid polyethylene glycols, and
mixtures thereof and in oils. Under ordinary conditions of storage
and use, these preparations may contain a preservative to prevent
the growth of microorganisms. Pharmaceutical compositions suitable
for injectable use include sterile aqueous solutions (where water
soluble) or dispersions and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersions. In all
cases, the composition must be sterile and must be fluid to the
extent that easy syringability exists. It must be stable under the
conditions of manufacture and storage and must be preserved against
the contaminating action of microorganisms such as bacteria and
fungi. The vehicle can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, liquid polyethylene glycol, and the
like), suitable mixtures thereof, and vegetable oils. The proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersion, and by the use of surfactants.
[0043] Prevention of the action of microorganisms can be achieved
by various antibacterial and antifungal agents, for example,
parabens, chlorobutanol, phenol, ascorbic acid thimerosal, and the
like. In some cases, it will be preferable to include isotonic
agents, for example, sugars, sodium chloride, or polyalcohols such
as mannitol and sorbitol, in the composition. Prolonged absorption
of the injectable compositions can be brought about by including in
the composition an agent which delays absorption, for example,
aluminum monostearate or gelatin.
[0044] Sterile injectable solutions can be prepared by
incorporating the therapeutic compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filter sterilization.
Generally, dispersions are prepared by incorporating the
therapeutic compound into a sterile vehicle which contains a basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and freeze-drying which yield a
powder of the active ingredient (i.e., the therapeutic compound)
optionally plus any additional desired ingredient from a previously
sterile-filtered solution thereof,
[0045] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
subjects to be treated; each unit containing a predetermined
quantity of therapeutic compound calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
vehicle, The specification for the dosage unit forms of the
invention are dictated by and directly dependent on (a) the unique
characteristics of the therapeutic compound and the particular
therapeutic effect to be achieved, and (b) the limitations inherent
in the art of compounding such a therapeutic compound for the
treatment of neurological conditions in subjects.
[0046] Therapeutic compositions can be administered in time-release
or depot form, to obtain sustained release of the therapeutic
compounds over time The therapeutic compounds of the invention can
also be administered transdermally (e.g., by providing the
therapeutic compound, with a suitable carrier, in patch form).
[0047] Active compounds are administered at a therapeutically
effective dosage sufficient to mitigate neurodegeneration and/or to
effect neuroprotection and/or cognition enhancement in a subject. A
"therapeutically effective dosage" preferably mitigates
neurodegeneration by about 20%, more preferably by about 40%, even
more preferably by about 60%, and still more preferably by about
80% relative to untreated subjects. The ability of a compound to
mitigate neurodegeneration can be evaluated in model systems that
may be predictive of efficacy in mitigating neurodegeneration in
human diseases, such as animal Model systems known in the art
(including, the method of transient middle cerebral artery
occlusion in the rat) or by in vitro methods, (including, e.g., the
assays described herein).
[0048] Carrier or substituent moieties useful in the present
invention may also include moieties that allow the therapeutic
compound to be selectively delivered to a target organ. For
example, delivery of the therapeutic compound to the brain may be
enhanced by a carrier moiety using either active or passive
transport (a "targeting moiety"). Illustratively, the carrier
molecule may be a redox moiety, as described in, for example, U.S.
Pat. Nos. 4,540,654 and 5,389,623, both to Bodor. These patents
disclose drugs linked to dihydropyridine moieties which can enter
the brain, where they are oxidized to a charged pyridinium species
which is trapped in the brain. Thus drugs accumulate in the brain.
Other carrier moieties include compounds, such as amino acids or
thyroxine, which can be passively or actively transported in vivo.
Such a carrier moiety can be metabolically removed in vivo, or can
remain intact as part of an active compound. Structural mimics of
amino acids (and other actively transported moieties) including
peptidomimetics, are also useful in the invention. As used herein,
the term "peptidomimetic" is intended to include peptide analogues
which serve as appropriate substitutes for peptides in interactions
with, for example, receptors and enzymes. The peptodomimetic must
possess not only affinity, but also efficacy and substrate
function. That is, a peptidomimetic exhibits functions of a
peptide, without restriction of structure to amino acid
constituents. Peptidomimetics, methods for their preparation and
use are described in Morgan et at, (1989), the contents of which
are incorporated herein by reference. Many targeting moieties are
known, and include, for example, asialoglycoproteins (see e.g., Wu,
U.S. Pat. No. 5,166,320) and other ligands which are transported
into cells via receptor-mediated endocytosis (see below for further
examples of targeting moieties which may be covalently or
non-covalently bound to a target molecule).
[0049] The compound 2-(4-methylthiazol-5-yl)ethyl nitrate maleate
salt can be synthesized by methods set forth herein (see, e.g.,
Working Examples) or as described in patents U.S. Pat. Nos.
5,807,847; 5,883,122; and 6,310,052. Various compounds for use in
the methods of the invention are commercially available and/or can
be synthesized by standard techniques. In general, nitrate esters
can be prepared from the corresponding alcohol, oxirane or alkene
by standard methods, that include: nitration of alcohols and
oxiranes, mixed aqueous/organic solvents using mixtures of nitric
and sulfuric acid and/or their salts, with temperature control (see
Yang et at., 1996); nitration of alcohols and oxiranes in acetic
anhydride using nitric acid or its salts with or without added acid
catalyst, with temperature control (see, e.g., Louw et al., 1976);
nitration of an alcohol with a nitronium sail, e.g. a
tetrafluoroborate; nitration of an alkene with thallium nitrate in
an appropriate solvent (see Ouellette el at., 1976).
[0050] The following Examples further illustrate the present
invention and are not intended to be limiting in any respect. Those
skilled in the art will recognize, or be able to ascertain using no
more than routine experimentation, numerous equivalents to the
specific procedures described herein. Such equivalents are
considered to be within the scope of this invention and are covered
by the claims.
WORKING EXAMPLES
Synthesis of 2-(4-methylthiazol-5-yl)ethyl Nitrate Maleate Salt
[0051] The synthesis of 2-(4-methylthiazol-5-yl)ethyl nitrate can
be found in U.S. Pat. No. 6,310,052. (Example 14), which is
incorporated herein by reference in its entirety. The synthetic
route employed for synthesis of 2-(4-methylthiazol-5-yl)ethyl
nitrate maleate salt is shown below:
##STR00005##
.sup.1H-NMR Spectroscopy
[0052] Nuclear magnetic resonance spectra were recorded on a Bruker
AM 400 Instrument at ambient temperature for
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt. The .sup.1H-NMR
spectrum and assignment are shown below (in D.sub.2O), which
conforms to the structure of 2-(4-methylthiazol-5-yl)ethyl nitrate
maleate salt.
TABLE-US-00001 ##STR00006## .sup.1H-NMR Measurement Chemical shifts
(.delta.) No. of protons Peak patterns Peak Assignments 2.38 3 s
H.sub.2 3.24 2 t H.sub.3 4.64 2 t H.sub.4 6.29 2 s H.sub.5 8.88 1 s
H.sub.1
.sup.13C-NMR Spectroscopy
[0053] Broadband decoupled .sup.13C-NMR spectrum was recorded for
2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt (in D.sub.2O).
The .sup.13C -NMR Spectrum and assignment are shown below, which
conforms to the structure of 2-(4-methylthiazol-5-yl)ethyl nitrate
maleate salt.
TABLE-US-00002 ##STR00007## .sup.13C-NMR Measurement Chemical
shifts (.delta.) Number of carbons Peak assignments 13.01 1 C.sub.3
23.51 1 C.sub.5 72.41 1 C.sub.6 126.97 1 C.sub.4 130.75 1 C.sub.7
149.25 1 C.sub.2 151.92 1 C.sub.1 167.81 1 C.sub.8
Mass Spectrometry
[0054] Electrospray ionization mass spectrometry (ESI-MS) analyses
were carried out on a Micromass ZQ-4000 single quadruple mass
spectrometer (Milford, Mass., USA) with positive ion charge.
Samples were suspended in ethanol and infused by a syringe pump at
10 .mu.L/min. The Micromass ZQ-4000 is a high resolution/accurate
mass instrument with positive and negative ion capability with a
mass range of 2000 Daltons at 10 kv. The MS spectrum and assignment
for 2-(4-methylthiazol-5-yl)ethyl nitrate maleate salt conformed to
the structure of 2-(4-methylthiazol-5-yl)ethyl nitrate maleate
salt.
DSC and TGA Testing
[0055] DSC methodology: The Perkin Elmer Pyris Diamond Differential
Scanning calorimeter was calibrated for temperature and energy with
high-purity indium and zinc. A 5-8 mg sample was precisely weighted
and sealed into an aluminum pan. The measurement was performed at a
heating rate of 20.degree. K./min in a high purity nitrogen
atmosphere. The result is shown below.
[0056] TGA methodology: The Perkin Elmer Pyris I Thermogravimetric
Analyzer was calibrated for temperature and weight using standard
materials. About 3-5 mg sample was taken for testing. The
measurement was carried out at a heating rate of 20.degree. K./min
in a high purity nitrogen atmosphere.
X-Ray Powder Diffraction
[0057] A thermo ARL X'tra powder diffractometer with Cu radiation
.lamda.=0.1542 nm was used. The measurement conditions were changed
from standard to high resolution and over an extended collection
period to improve detect ability of potential crystalline
impurities. The samples were analyzed as-is, with no grinding or
other pre-treatment conducted prior to analysis. Analyses were
performed from 3-50 degree 2-theta using the following conditions:
divergence slit: 0.9 mm; anti-scatter slit: 0.3 mm; receiving slit:
0.1 mm; detector slit: 0.6 mm; scan rate: 3 degree/min. A typical
XRPD graphic scan of 2(4-methylthiazol-5-yl)ethyl nitrate maleate
salt is shown in FIG. 1.
Formulations
[0058] The compound 2-(4-methylthiazol-5-yl)ethyl nitrate maleate
salt was formulated as follows:
TABLE-US-00003 Component % g 2-(4-methylthiazol-5-yl)ethyl 30.00%
4.55 nitrate maleate salt Methocel K100M 35.75% 5.42 Avicel PH 102
23.50% 3.56 Povidone 10.00% 1.52 Cab-O-Sil 0.25% 0.038 Magnesium
Stearate 0.50% 0.076 Total 100.00% 15.17
TABLE-US-00004 Component % g 2-(4-methylthiazol-5-yl)ethyl 40.00%
7.10 nitrate maleate salt Methocel K100M 25.75% 4.57 Avicel PH 102
23.50% 4.17 Povidone 10.00% 1.78 Cab-O-Sil 0.25% 0.044 Magnesium
Stearate 0.50% 0.089 Total 100.00% 17.75
TABLE-US-00005 Component % g 2-(4-methylthiazol-5-yl)ethyl 40.00%
7.10 nitrate maleate salt Ethocel 100 Premium 25.75% 4.57 Avicel PH
102 23.50% 4.17 Povidone 10.00% 1.78 Cab-O-Sil 0.25% 0.044
Magnesium Stearate 0.50% 0.089 Total 100.00% 17.75
[0059] Using a Korsch XL 100 Press, the formulations described
above were pressed into a dry tablet for oral use. The maleate salt
provided herein has processing advantages over other salts (e.g.,
the chloride, phosphate, mesylate, and sulfate salts) in the
preparation of a dry tablet.
REFERENCES
[0060] Arancio, O., E. R. Kandel, R. D. Hawkins,
"Activity-dependent long-term enhancement of transmitter release by
presynaptic 3',5'-cyclic GMP in cultured hippocampal neurons",
Nature 376 (1995) 74-80.
[0061] Barger, S. W., R. R. Riscus, P. Ruth, F. Hofmann, M. P.
Mattson, "Role of cyclic GMP in the regulation of neuronal calcium
and survival by secreted forms of .beta,-amyloid precursor
protein", J. Neurochem. 64 (1995) 2087-2096.
[0062] Bernabeu, R. N. Schroder, J. Quevedo, M. Cammarota, I.
Izquierdo, J. H. Medina, "Further evidence for the involvement of a
hippocampal cGMP/cGMP-dependent protein kinase cascade in memory
consolidation", NeuroReport 8 (1997) 2221-2224.
[0063] Bernabeu, R. P. Schmitz, M. P. Faillace, I. Izquierdo, J. H.
Medina, "Hippocampal cGMP and cAMP are differentially involved in
memory processing of inhibitory avoidance learning", NeuroReport 7
(1996) 585-588.
[0064] Briscoe et al., Am. J Physiol. 1233 (1995) 134.
[0065] Bullock, R., A Zauner, J. J. Woodward, J. Nyseros, S. C.
Choi, J. D. Ward, A.
[0066] Marmarou, H. F. Young, "Factors affecting, excitatory amino
acid release following severe human head injury". J. Neurosurg. 89
(1998) 507-518.
[0067] Chan, P. H., M. Kawase, K. Murakami, S. F. Chen, Y, Li, B.
Calagui, L. Reola, E. Carlson, C. J. Epstein, "Overexpression of
SOD1 in transgenic rats protects vulnerable neurons against
ischemic damage after global cerebral ischemia and reperfusion", J.
Neurosic, 18 (1998) 8292-8299.
[0068] Chen, J., T. Nagayama, K. Jin, R. A. Stetler, R. L. Zhu, S.
H. Graham, R. P. Simon, "Induction of caspase-3-like protease may
mediate delayed neuronal death in the hippocampus after transient
cerebral ischemia", J. Neurosci. 18 (1998) 4914-4928.
[0069] Cohen, G. M., "Caspases: the executioners of aopotosis",
Biochem, J. 326 (1997) 1-16.
[0070] Du, Y., K. R. Bales, R. C. Dodd, E. Hamilton-Byrd, J. W.
Horn, D. L. Czilli, L. K. Simmons, B. Ni, S. M. Paul, "Activation
of a caspase-3-related cysteine protease is required for
glutamate-mediated. apoptosis of cultured cerebellar granule
neurons", Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 11657-11662.
[0071] Endres, M., S. Namura, M. Shimizu-Sasamata, C. Waebar, L.
Zhang, T. Gomez-Isla, B. T. Hyman, M. A. Moskowitz, "Attenuation of
delayed neuronal death after mild focal ischemia in mice by
inhibition of the caspase family", J. Cereb. Blood Flow Metal). 18
(1998)238-247.
[0072] Estevez, A. G., N. Spear, J. A. Thompson, T. L. Cornwell, R.
Radi, L. Barbeito, J. S. Beckman, "Nitric oxide-dependent
production of cGMP supports the survival of rat embryonic motor
neurons cultured with brain-derived neurotrophic factor", J.
Neurosci. 18 (1998) 3708-3714.
[0073] Farinelli, S. E., D. S. Park, L. A. Greene, "Nitric oxide
delays the death of trophic factor-deprived PC12 cells and
sympathetic neurons by a cGMP-mediated mechanism", J. Neurosci. 16
(1996) 23-25-2234.
[0074] Furukawa, K,, S. W. Barger, E. M. Blalock, M. P. Mattson,
"Activation of K.sup.-+ channels and suppression of neuronal
activity by secreted .beta.-amyloid precursor protein", Nature 379
(1996) 74-78.
[0075] Gaetani, P., A. Pasqualin, R. Rodriguez y Baena, E. Borasio,
F. Marzatico, "Oxidative stress in the human brain after
subarachnoid hemorrhage", J. Neurosurg. 89 (1998) 748-754.
[0076] Goda, H., H. Ooboshi, H. Nakane, S. Ibayashi, S. Sadoshima,
M. Fujishima, "Modulation of ischemia-evoked release of excitatory
and inhibitory amino acids by adenosine Al receptor agonist", Eur.
Pharmacol. 357 (1998) 149-155,
[0077] Gottron, F. J., H. S. Ying. D. W. Choi, "Caspase inhibition
selectively reduces the apoptotic component of oxygen-glucose
deprivation-induced cortical neuronal cell death". Mol. Cell.
Neurosci, 9 (1.997) 159-169.
[0078] Haviv, R. L. Lindenboim, H. Li, J. Yuan, R. Stein, "Need for
caspases in apoptosis of trophic factor-deprived PC12 cells", J.
Neurosci. Res. 50 (1997) 69-80.
[0079] Higashi et al Neuropathol. Appl. Neurobiol. 21(1995)
480-483,
[0080] Huang, F. P., L. F. Zhou, C. Y. Yang, "Effects of mild
hypothermia on the release of regional glutamate and glycine during
extended transient focal cerebral ischemia in rats", Neurochem.
Res. 23 (1998) 991-996.
[0081] Ibarrola, D., H. Seegers. A. Jaillard, M. Hommel, M.
Decorps, R. Massarelli, "The effect of eliprodil on the evolution
of a focal cerebral ischaemia in vivo", Fur, J. Pharmacol, 352
(1998) 29-35.
[0082] Jiang el at., Cereb. Blood Flow Metab. 18 (1998)
758-767.
[0083] Kesner, NIDA Res. Monographs 97 (1990) 22-36.
[0084] Kim, Y. M., R. V. Talanian, T. R. Billiar, "Nitric oxide
inhibits apoptosis by preventing increases in caspase-3-like
activity via two distinct mechanisms", J. Biol. Chem. 272 (1997)
31138-31148.
[0085] Louw, R., H. P. W. Vermeeren, J. J. A. Van Asten, W. J.
Ultee, J. Chem. Soc., Chem. Comm. (1976) 496-497
[0086] Macdonald, R. L., M. Stoodley, "Pathophysiology of cerebral
ischemia", Neural. Med. Chir. (Tokyo) 38 (1998) 1-11.
[0087] Mattson and Scheff, J. Neurotrauma 11(1994) 3-33.
[0088] Mizuno, A., K. Umemura, M. Nakashima, "Inhibitory effect of
MCI-186, a free radical scavenger, on cerebral ischemia following
rat middle cerebral artery occlusion", Gen. Pharmacol. 30 (1998)
575-578.
[0089] Mordenti, "Man versus beast: Pharmacokinetic scaling in
mammals", J. Pharm. Sci. 75 (1986) 1028-1040.
[0090] Morgan et at., "Approaches to the discovery of non-peptide
ligands for peptide receptors and peptidases", In Ann. Rep, Med.
Chem. (Virick F. J., et at) (1989) pp. 243-253, Academic Press, San
Diego, Calif.
[0091] Namura, S., I. Zhu, K. Fink, M. Endres, A Srinivasan, K. I.
Tomaselli, I. Yuan, M. A. Moskowitz, "Activation and cleavage of
caspase-3 in apoptosis induced by experimental cerebral ischemia",
J. Neurosci. 18 (1998) 3659-3668.
[0092] Ni, B., X. Wu, Y. Su, D. Stephenson, E. B. Smalstig, J.
Clemens, S. M. Paul, "Transient global forebrain ischemia induces a
prolonged expression of the caspase-3 mRNA in rat hippocampal CA1
pyramidal neurons", J. Cereb. Blood How Metal). 18 (1998)
248-256.
[0093] Nicholson, D. W., N. A. Thornberry, "Caspases killer
proteases", Trends Biochem. Sci. 22 (1997) 299-306.
[0094] O'Neill, M. J., A. Bond, P. L. Ornstein, M. A. Ward, C. A.
Flicks, K. Hoo, D. Bleakman, D. Lodge, "Decahydrosioquinolines:
novel competitive AMPA/kainate antagonists with neuroprotective
effects in global cerebral ischaemia", Neuropharmacol. 37 (1998)
1211-1222,
[0095] Ouellette, R. J., R. J. Bertsch, J. Org. Chem. 41(1976)
2782-2783.
[0096] Owais, M. et a., Antimicrob. Agents Chemother. 39 (1995)
180.
[0097] Ranade, V. V., J, Clin. Pharmacol. 29 (1989) 685.
[0098] Tagami, M. K. Yamagata, K. Ikeda, Y. Nara, H. Fujino, A.
Kobota, F. Numano, Y. Yamori, "Vitamin E prevents apoptosis in
cortical neurons during hypoxia and oxygen reperfusion", Lab.
Invest. 78 (1998) 1415-1429.
[0099] Umemura, K., A. Shimakura, M. Nakashima, "Neuroprotective
effect of a novel AMPA receptor antagonist, YM90K, in a rat focal
cerebral ischaemia", Brain Res. 773 (1997) 61-65.
[0100] Umezawa et al., Biochem. Biophys. Res. Commun. 153 (1988)
1038.
[0101] Venault, P. G. Chapouthier, L., Prado de Carvalho and
Rossier, J., Encephale, 18 (1992) 655.
[0102] Wittkowsky, Pharmacotherapy 18 (1998) 945-1005.
[0103] Wu, J., Y. Wang, M. J. Rowan, R. Anwyl, "Evidence for
involvement of the cGMP-protein kinase G signaling system in the
induction of long-term depression, but not long-term potentiation,
in the dentate gyrus in vitro", J. Neurosci. 18 (1998)
3589-3596.
[0104] Yang, K J. D. Artz, J. Lock, C. Sanchez, B. M. Bennett, A.
B. Fraser, G. R. Thatcher, J. Chem. Soc., Perkin Trans. 1 (1996)
1073-1075.
[0105] Yang, Y. L., W. H. Pan, T. Chiu, M. T. Lin, "Striatal
glutamate release is important for development os ischemic damage
to strital neurons during rat heatstroke", Brain Res. 795 (1998)
21-127.
* * * * *